Study Description
This is a prospective Phase II multi-center study with an upfront 16-week, randomized,
double-blind, placebo-controlled period, and extension periods, to assess the efficacy,
safety and pharmacokinetics of alpelisib in pediatric and adult participants with
PIK3CA-related overgrowth spectrum (PROS). This study consists of a screening period of up to 42 days, core period of 24 weeks,
extension period of 24 weeks and long-term extension period of up to approximately 5
years. The study will enroll adult participants (Group 1), 6-17 years old pediatric
participants (Group 2), two exploratory sets of 2-5 years old pediatric participants
(Group 3 treated with granules and Group 4 treated with film-coated tablets (FCT)) ) and
an exploratory group of 6 to 17 years old pediatric participants (Group 5; treated with
FCT [at a higher starting dose than Group 2]).
Eligible participants aged ≥6 years old will be randomized in a 2:1 ratio to alpelisib or
matching placebo. Both age groups (group 1 and group 2) will be enrolled in the study in
parallel. In the core period, participants will receive treatment in blinded fashion,
with an upfront 16-week placebo-controlled period. After Week 16 those participants who
were randomized to receive placebo will be switched to active treatment with alpelisib.
Those participants who were randomized to receive alpelisib will continue their active
treatment.
Participants in Group 4 will be enrolled before Group 3. Group 5 will be open to
enrollment after enrollment of Group 2 has been completed. All participants will receive
alpelisib in an open-label setting.
Group 3 will be enrolled later, after the completion of the primary analysis when the
efficacy, safety and PK data will be available from the participants in Groups 1 and 2 in
addition to the data from Group 4 and 5 as available, in order to select the recommended
dose for participants in Group 3.
The planned duration of alpelisib treatment in the study will be up to 5 years after
randomization/treatment start for all age groups. Participant may be discontinued from
treatment with alpelisib earlier due to unacceptable toxicity, confirmed disease
progression, death, and/or any other reason at the discretion of the investigator or the
participant.
Interventions
Alpelisib
Placebo
Eligibility Criteria
Inclusion Criteria:
1. Signed informed consent and assent (when applicable) from the patient, parent, legal
authorized representative or guardian prior to any study related screening
procedures are performed
2. Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth and
at least one measurable PROS-related lesion confirmed by blinded independent review
committee (BIRC) assessment
3. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local
laboratories
4. A tissue sample (fresh or archival) is be sent to a Novartis-designated central
laboratory. If archival tissue is not available, collection of a fresh tissue biopsy
is required for participants in Groups 1, 2 and 5, if it is not clinically
contraindicated. For participants in Groups 3 and 4, a fresh tissue biopsy is not
mandatory.
For China only: Tissue sample collection and biomarker assessments are not
applicable.
For Germany only: If archival tissue is available, it must be sent to a Novartis
designated central laboratory. If no archival tissue is available, obtaining a fresh
tissue biopsy is recommended, if it is not clinically contraindicated, but is not
mandatory.
5. Karnofsky (in patients > 16 years old at study entry)/Lansky (≤16 yrs of age at
study entry) performance status index ≥50
6. Adequate bone marrow and organ function including Fasting plasma glucose (FPG) ≤ 140
mg/dL (7.7 mmol/L) and Glycosylated hemoglobin (HbA1c) ≤ 6.5% (both criteria have to
be met) (as assessed by central laboratory for eligibility)
7. Presence of at least one PROS-related measurable lesion defined as a lesion with
longest diameter ≥2 cm, when the volume can be accurately and reproducibly measured
by MRI (Magnetic resonance imaging), and associated with complaints, clinical
symptoms or functional limitations affecting the patient's everyday life.
Measurability must be confirmed by BIRC before randomization.
Exclusion Criteria:
1. Participant with only isolated macrodactyly, skin nevus/nevi and macroencephaly (the
only clinical feature or a combination of any of three of them), in absence of other
PROS-related lesions at the time of informed consent
2. Previous treatment with alpelisib and/or any other PI3K inhibitor(s) (except
treatment attempt, defined as the attempt to treat PROS with any of PI3K inhibitors,
with treatment duration less than 2 weeks and stopped at least 4 weeks prior to the
first dose of study medication with alpelisib)
3. Radiation exposure for PROS treatment purpose within the previous 12 months on those
PROS areas which are expected to qualify for target lesions (except lesion(s)
progressing after completion of radiotherapy) at time of informed consent.
4. Debulking or other major surgery performed within 3 months at time of informed
consent
5. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE
v.4.03) within 30 days before informed consent, and/or sclerotherapy/embolization
for vascular complications performed within 6 weeks before informed consent. Note:
Participants receiving anticoagulants for PROS-related coagulopathy, primary or
secondary prophylaxis of thrombosis may be included in the study
6. Participants in Groups 1, 2 ad 5 with documented pneumonitis or interstitial lung
disease at time of informed consent and with impaired lung function (e.g., FEV1 or
DLCO ≤ 70% of predicted) that is not related to PROS. Participants in Groups 3 and 4
with documented or suspicious pneumonitis or interstitial lung disease based on MRI
images at time of informed consent
7. History of acute pancreatitis within 1 year before informed consent or past medical
history of chronic pancreatitis at time of informed consent
8. Participants with an established diagnosis of type I diabetes mellitus or
uncontrolled type II diabetes mellitus at time of informed consent
9. Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum at
time of informed consent, when epilepsy is not controlled and/or the patient may not
be switched to non-enzyme inducing antiepileptic drug(s) at time of informed
consent.
10. Participants with clinically significant worsening of PROS-related laboratory
anomalies, physical signs and symptoms (such as, but not limited to increase of
D-dimers, worsening of underlying pain, newly occurring swelling or redness)
indicating an uncontrolled condition during the screening phase, particularly if
systemic treatment with any other inhibitor of the PI3K/AKT/mTOR pathway was stopped
prior to the start of study treatment. This includes but is not limited to
hypercoagulability state in participants not receiving prophylactic treatment.
Other inclusion/exclusion criteria may apply
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